tbuckley/cabot-search huggingface dataset:
Noninvasive Evaluation of Cardiac Chamber Pressures Using Subharmonic-Aided Pressure Estimation With Definity Microbubbles
Authors: Cara Esposito, Priscilla Machado, Maureen E. McDonald, Michael P. Savage, David Fischman, Praveen Mehrotra, Ira S. Cohen, Nicholas Ruggiero, Paul Walinsky, Alec Vishnevsky, Kristopher Dickie, Marguerite Davis, Flemming Forsberg, Jaydev K. Dave
Journal: JACC. Cardiovascular imaging (2022)
Tfh cells and the germinal center are required for memory B cell formation &amp; humoral immunity after ChAdOx1 nCoV-19 vaccination
Authors: William S. Foster, Jia Le Lee, Nazia Thakur, Joseph Newman, Alexandra J. Spencer, Sophie Davies, Danielle Woods, Leila Godfrey, Iain M. Hay, Silvia Innocentin, Juan Carlos Yam-Puc, Emily C. Horner, Hayley J. Sharpe, James E. Thaventhiran, Dalan Bailey, Teresa Lambe, Michelle A. Linterman
Journal: Cell Reports Medicine (2022)

Emergence from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been facilitated by the rollout of effective vaccines. Successful vaccines generate high-affinity plasma blasts and long-lived protective memory B cells. Here, we show a requirement for T follicular helper (Tfh) cells and the germinal center reaction for optimal serum antibody and memory B cell formation after ChAdOx1 nCoV-19 vaccination. We found that Tfh cells play an important role in expanding antigen-specific B cells while identifying Tfh-cell-dependent and -independent memory B cell subsets. Upon secondary vaccination, germinal center B cells generated during primary immunizations can be recalled as germinal center B cells again. Likewise, primary immunization GC-Tfh cells can be recalled as either Tfh or Th1 cells, highlighting the pluripotent nature of Tfh cell memory. This study demonstrates that ChAdOx1 nCoV-19-induced germinal centers are a critical source of humoral immunity.
Hypoaminoacidemia underpins glucagon-mediated energy expenditure and weight loss
Authors: David C.D. Hope, Charlotte E. Hinds, Tatiana Lopes, Matthew L. Vincent, Jed V. Shrewsbury, Arthur T.C. Yu, Iona Davies, Rebecca Scott, Ben Jones, Kevin G. Murphy, James S. Minnion, Alessandro Sardini, David Carling, Thomas A. Lutz, Stephen R. Bloom, Tricia M.M. Tan, Bryn M. Owen
Journal: Cell Reports Medicine (2022)

Glucagon analogs show promise as components of next-generation, multi-target, anti-obesity therapeutics. The biology of chronic glucagon treatment, in particular, its ability to induce energy expenditure and weight loss, remains poorly understood. Using a long-acting glucagon analog, G108, we demonstrate that glucagon-mediated body weight loss is intrinsically linked to the hypoaminoacidemia associated with its known amino acid catabolic action. Mechanistic studies reveal an energy-consuming response to low plasma amino acids in G108-treated mice, prevented by dietary amino acid supplementation and mimicked by a rationally designed low amino acid diet. Therefore, low plasma amino acids are a pre-requisite for G108-mediated energy expenditure and weight loss. However, preventing hypoaminoacidemia with additional dietary protein does not affect the ability of G108 to improve glycemia or hepatic steatosis in obese mice. These studies provide a mechanism for glucagon-mediated weight loss and confirm the hepatic glucagon receptor as an attractive molecular target for metabolic disease therapeutics.
Eosinophil depletion with benralizumab is associated with attenuated mannitol airway hyperresponsiveness in severe uncontrolled eosinophilic asthma
Authors: Rory Chan, Chris RuiWen Kuo, Sunny Jabbal, Brian J. Lipworth
Journal: Journal of Allergy and Clinical Immunology (2022)

Airway hyperresponsiveness (AHR) and eosinophilia are hallmarks of persistent asthma.We investigated whether eosinophil depletion with benralizumab might attenuate indirect mannitol AHR in severe uncontrolled asthma using a pragmatic open-label design.After a 4-week run-in period with provision of usual inhaled corticosteroids and/or long-acting β-agonist (baseline), adults with mannitol-responsive uncontrolled severe eosinophilic asthma received 3 doses of open-label benralizumab 30 mg every 4 weeks, followed by 16 weeks' washout after the last dose. The primary outcome was doubling difference (DD) in provocative dose of mannitol required to decrease FEV1 by 10% (PD10) at the end point after 12 weeks, powered at 90% with 18 patients required to detect 1 DD. Secondary outcomes included measures assessed by the asthma control questionnaire and mini-asthma quality of life questionnaire.Twenty-one patients completed 12 weeks' benralizumab therapy at the end point at week 12. Mean (SEM) age was 53 (4) years, and FEV1 80.2% (4.1%) inhaled corticosteroid dose was 1895 (59) μg, with 12 receiving long-acting muscarinic antagonist and 13 leukotriene receptor antagonists. Improvement in AHR was significant by 8 weeks, with a mean 2.1 DD (95% confidence interval 1.0, 3.3; P < .01) change in PD10 at week 12, while mean changes in asthma control questionnaire and mini-asthma quality of life questionnaire were significant by week 2 and sustained over 12 weeks, both exceeding the minimal important difference. Peripheral blood eosinophils were depleted by 2 weeks (439 to 6 cells/μL). No significant improvement occurred in lung function after 12 weeks. Domiciliary peak flow and symptoms also improved with benralizumab.Eosinophil depletion results in clinically meaningful attenuated AHR in severe uncontrolled asthma patients.
Cellular and Molecular Mechanisms of MEK1 Inhibitor–Induced Cardiotoxicity
Authors: Tyler C. Beck, Dimitrios C. Arhontoulis, Jordan E. Morningstar, Nathaniel Hyams, Andrew Stoddard, Kendra Springs, Rupak Mukherjee, Kris Helke, Lilong Guo, Kelsey Moore, Cortney Gensemer, Rachel Biggs, Taylor Petrucci, Jennie Kwon, Kristina Stayer, Natalie Koren, Andrew Harvey, Heather Holman, Jaclyn Dunne, Diana Fulmer, Ayesha Vohra, Le Mai, Sarah Dooley, Julianna Weninger, Silvia Vaena, Martin Romeo, Robin C. Muise-Helmericks, Ying Mei, Russell A. Norris
Journal: JACC CardioOncology (2022)

Trametinib is a MEK1 (mitogen-activated extracellular signal-related kinase kinase 1) inhibitor used in the treatment of BRAF (rapid accelerated fibrosarcoma B-type)–mutated metastatic melanoma. Roughly 11% of patients develop cardiomyopathy following long-term trametinib exposure. Although described clinically, the molecular landscape of trametinib cardiotoxicity has not been characterized. The aim of this study was to test the hypothesis that trametinib promotes widespread transcriptomic and cellular changes consistent with oxidative stress and impairs cardiac function. Mice were treated with trametinib (1 mg/kg/d). Echocardiography was performed pre- and post-treatment. Gross, histopathologic, and biochemical assessments were performed to probe for molecular and cellular changes. Human cardiac organoids were used as an in vitro measurement of cardiotoxicity and recovery. Long-term administration of trametinib was associated with significant reductions in survival and left ventricular ejection fraction. Histologic analyses of the heart revealed myocardial vacuolization and calcification in 28% of animals. Bulk RNA sequencing identified 435 differentially expressed genes and 116 differential signaling pathways following trametinib treatment. Upstream gene analysis predicted interleukin-6 as a regulator of 17 relevant differentially expressed genes, suggestive of PI3K/AKT and JAK/STAT activation, which was subsequently validated. Trametinib hearts displayed elevated markers of oxidative stress, myofibrillar degeneration, an 11-fold down-regulation of the apelin receptor, and connexin-43 mislocalization. To confirm the direct cardiotoxic effects of trametinib, human cardiac organoids were treated for 6 days, followed by a 6-day media-only recovery. Trametinib-treated organoids exhibited reductions in diameter and contractility, followed by partial recovery with removal of treatment. These data describe pathologic changes observed in trametinib cardiotoxicity, supporting the exploration of drug holidays and alternative pharmacologic strategies for disease prevention.
Doxorubicin hydrochloride and L-arginine co-loaded nanovesicle for drug resistance reversal stimulated by near-infrared light
Authors: Linping Jiang, Kesi Wang, Liyan Qiu
Journal: Asian Journal of Pharmaceutical Sciences (2022)

Drug resistance is accountable for the inadequate outcome of chemotherapy in clinics. The newly emerging role of nitric oxide (NO) to conquer drug resistance has been recognized as a potential strategy. However, it remains a great challenge to realize targeted delivery as well as accurate release of NO at desired sites. Herein, we developed a PEGylated indocyanine green (mPEG-ICG) integrated nanovesicle system (PIDA) to simultaneously load doxorubicin hydrochloride (DOX⋅HCl) and the NO donor L-arginine (L-Arg), which can produce NO triggered by NIR light irradiation and exert multimodal therapy to sensitize drug-resistant cancers. Upon 808 nm irradiation, the NO released from PIDA led to a decrease in mitochondrial membrane potential, an increase in ROS and significant ATP depletion in K562/ADR cells, thus inhibiting cell growth and resolving the problem of drug resistance. Consequently, the in vivo experiment on K562/ADR-bearing nude mice indicated that PIDA nanovesicles achieved significant anticancer efficacy with a tumor inhibition rate of 80.8%. Above all, PIDA nanovesicles offer guidance for designing nanoplatforms for drug-resistant cancer treatment.
Influence of viral genome properties on polymerase fidelity
Authors: Gabriel Dupré, Romain Volmer
Journal: Trends in Genetics (2022)

The first step of viral evolution takes place during genome replication via the error-prone viral polymerase. Among the mutants that arise through this process, only a few well-adapted variants will be selected by natural selection, renewing the viral genome population. Viral polymerase-mediated errors are thought to occur stochastically. However, accumulating evidence suggests that viral polymerase-mediated mutations are heterogeneously distributed throughout the viral genome. Here, we review work that supports this concept and provides mechanistic insights into how specific features of the viral genome could modulate viral polymerase-mediated errors. A predisposition to accumulate viral polymerase-mediated errors at specific loci in the viral genome may guide evolution to specific pathways, thus opening new directions of research to better understand viral evolutionary dynamics.
European Groundshot—addressing Europe's cancer research challenges: a Lancet Oncology Commission
Authors: Mark Lawler, Lynne Davies, Simon Oberst, Kathy Oliver, Alexander Eggermont, Anna Schmutz, Carlo La Vecchia, Claudia Allemani, Yolande Lievens, Peter Naredi, Tanja Cufer, Ajay Aggarwal, Matti Aapro, Kathi Apostolidis, Anne-Marie Baird, Fatima Cardoso, Andreas Charalambous, Michel P Coleman, Alberto Costa, Mirjam Crul, Csaba L Dégi, Federica Di Nicolantonio, Sema Erdem, Marius Geanta, Jan Geissler, Jacek Jassem, Beata Jagielska, Bengt Jonsson, Daniel Kelly, Olaf Kelm, Teodora Kolarova, Tezer Kutluk, Grant Lewison, Françoise Meunier, Jana Pelouchova, Thierry Philip, Richard Price, Beate Rau, Isabel T Rubio, Peter Selby, Maja Južnič Sotlar, Gilliosa Spurrier-Bernard, Jolanda C van Hoeve, Eduard Vrdoljak, Willien Westerhuis, Urszula Wojciechowska, Richard Sullivan
Journal: The Lancet Oncology (2022)
Lung Ultrasound Evaluation of SCAI Shock Stages Predicts Mortality in ST-Segment Elevation Myocardial Infarction
Authors: Fernando Luís Scolari, Guilherme Pinheiro Machado, Alan Pagnoncelli, Angelo Chies, Gustavo Neves de Araujo, Anderson Donelli da Silveira, Sandro Cadaval Gonçalves, Alexander G. Truesdell, Filio Billia, Marco Vugman Wainstein, Rodrigo Vugman Wainstein
Journal: JACC. Cardiovascular imaging (2022)
Delivery of coenzyme Q10 loaded micelle targets mitochondrial ROS and enhances efficiency of mesenchymal stem cell therapy in intervertebral disc degeneration
Authors: Junyuan Sun, Fei Yang, Lianlei Wang, Haichao Yu, Zhijie Yang, Jingjing Wei, Krasimir Vasilev, Xuesong Zhang, Xinyu Liu, Yunpeng Zhao
Journal: Bioactive Materials (2022)

Stem cell transplantation has been proved a promising therapeutic instrument in intervertebral disc degeneration (IVDD). However, the elevation of oxidative stress in the degenerated region impairs the efficiency of mesenchymal stem cells (BMSCs) transplantation treatment via exaggeration of mitochondrial ROS and promotion of BMSCs apoptosis. Herein, we applied an emulsion-confined assembly method to encapsulate Coenzyme Q10 (Co-Q10), a promising hydrophobic antioxidant which targets mitochondria ROS, into the lecithin micelles, which renders the insoluble Co-Q10 dispersible in water as stable colloids. These micelles are injectable, which displayed efficient ability to facilitate Co-Q10 to get into BMSCs in vitro, and exhibited prolonged release of Co-Q10 in intervertebral disc tissue of animal models. Compared to mere use of Co-Q10, the Co-Q10 loaded micelle possessed better bioactivities, which elevated the viability, restored mitochondrial structure as well as function, and enhanced production of ECM components in rat BMSCs. Moreover, it is demonstrated that the injection of this micelle with BMSCs retained disc height and alleviated IVDD in a rat needle puncture model. Therefore, these Co-Q10 loaded micelles play a protective role in cell survival and differentiation through antagonizing mitochondrial ROS, and might be a potential therapeutic agent for IVDD.
Genome-wide admixture and association analysis identifies African ancestry–specific risk loci of eosinophilic esophagitis in African Americans
Authors: Yadu Gautam, Julie Caldwell, Leah Kottyan, Mirna Chehade, Evan S. Dellon, Marc E. Rothenberg, Tesfaye B. Mersha, Joshua Wechsler, Carla Davis, Glenn Furuta, Paneez Khoury, Seema Aceves, Sandeep K. Gupta, Jonathan Spergel, John Leung, Paul Menard-Katcher, Gary Falk, Ikuo Hirano, Nirmala Prabu Gonsalves, Kathryn Peterson
Journal: Journal of Allergy and Clinical Immunology (2022)
Cancer cells co-opt nociceptive nerves to thrive in nutrient-poor environments and upon nutrient-starvation therapies
Authors: Yu Zhang, Chengzhong Lin, Zheqi Liu, Yiting Sun, Mingtao Chen, Yibo Guo, Wei Liu, Chenping Zhang, Wantao Chen, Jian Sun, Ronghui Xia, Yuhua Hu, Xi Yang, Jiang Li, Zhiyuan Zhang, Wei Cao, Shuyang Sun, Xu Wang, Tong Ji
Journal: Cell Metabolism (2022)
Prevalence, Treatment, and Prognosis of Tumor Thrombi in Renal Cell Carcinoma
Authors: Fleur H.J. Kaptein, Tom van der Hulle, Sander J.E. Braken, Erik J. van Gennep, Jeroen T. Buijs, Mark C. Burgmans, Suzanne C. Cannegieter, Emma M.E. du Chatinier, Menno V. Huisman, Els L. van Persijn van Meerten, Henri H. Versteeg, Rob C.M. Pelger, Frederikus A. Klok
Journal: JACC CardioOncology (2022)

Renal cell carcinoma (RCC) can be complicated by a venous tumor thrombus (TT), of which the optimal management is unknown.This study sought to assess the prevalence of TT in RCC, its current management, and its association with venous thromboembolism (VTE), arterial thromboembolism (ATE), major bleeding (MB), and mortality.Patients diagnosed with RCC between 2010 and 2019 in our hospital were included and followed from RCC diagnosis until 2 years after, or until an outcome of interest (VTE, ATE, and MB) or death occurred, depending on the analysis. Cumulative incidences were estimated with death as a competing risk. Cause-specific hazard models were used to identify predictors and the prognostic impact.Of the 647 patients, 86 had a TT (prevalence 13.3%) at RCC diagnosis, of which 34 were limited to the renal vein, 37 were limited to the inferior vena cava below the diaphragm, and 15 extended above the diaphragm; 20 patients started therapeutic anticoagulation and 45 underwent thrombectomy with/without anticoagulation. During follow-up (median 24.0 [IQR: 7.0-24.0] months), 17 TT patients developed a VTE, 0 developed an ATE, and 11 developed MB. TT patients were more often diagnosed with VTE (adjusted HR: 6.61; 95% CI: 3.18-13.73) than non-TT patients, with increasing VTE risks in more proximal TT levels. TT patients receiving anticoagulation still developed VTE (HR: 0.56; 95% CI: 0.13-2.48), at the cost of more MB events (HR: 3.44; 95% CI: 0.95-12.42) compared with those without anticoagulation.Patients with RCC-associated TT were at high risk of developing VTE. Future studies should establish which of these patients benefit from anticoagulation therapy.
Performance Status and Long-Term Outcomes in Cancer-Associated Pulmonary Embolism
Authors: Ioannis T. Farmakis, Stefano Barco, Anna C. Mavromanoli, Stavros V. Konstantinides, Luca Valerio
Journal: JACC CardioOncology (2022)

Performance status (PS) is a reliable prognostic tool for overall survival in patients with cancer-associated pulmonary embolism (PE). However, its association with venous thromboembolism (VTE) recurrence and bleeding remains unclear.The aim of this study was to investigate whether PS at the time of PE diagnosis and its course during follow-up are linked to VTE-related outcomes.In this post hoc analysis of the Hokusai-VTE Cancer study, multivariable survival analysis was used to examine the association of PS with anticoagulation discontinuation and the composite primary outcome of VTE recurrence or major bleeding in patients with cancer-associated PE. PS was assessed using the Eastern Cooperative Oncology Group (ECOG) scale at baseline and at predefined study follow-up visits.Overall, 652 patients with cancer-associated PE were included. During 12-month follow-up, PS worsened in 317 of 642 patients (49.4%) with complete ECOG data at the end of follow-up. Those with worse ECOG values over follow-up were more likely to discontinue anticoagulation for any reason apart from death (adjusted HR: 1.59; 95% CI: 1.31-1.93). The composite primary outcome occurred in 57 of 500 patients with baseline ECOG status 0 or 1 and in 32 of 152 patients with ECOG status 2 (cumulative incidence at 12 months 10.7% [95% CI: 8.2%-13.9%] vs 14.4% [95% CI: 9.7%-21.3%]). Worse ECOG values during follow-up were associated with greater risk for the composite outcome (adjusted HR: 2.13; 95% CI: 1.24-3.67).ECOG PS is a valuable indicator for predicting VTE-related outcomes and may inform decision making regarding anticoagulation during follow-up in patients with cancer-associated PE.
The commercial antibiotics with inherent AIE feature: In situ visualization of antibiotic metabolism and specifically differentiation of bacterial species and broad-spectrum therapy
Authors: Bingnan Wang, Lirong Wang, Haozhong Wu, Xiaolin Liu, Jiamiao Zhu, Rong Hu, Dan Ding, Anjun Qin, Ben Zhong Tang
Journal: Bioactive Materials (2022)

The research on pharmacology usually focuses on the structure-activity relationships of drugs, such as antibiotics, to enhance their activity, but often ignores their optical properties. However, investigating the photophysical properties of drugs is of great significance because they could be used to in situ visualize their positions and help us to understand their working metabolism. In this work, we identified a class of commercialized antibiotics, such as levofloxacin, norfloxacin, and moxifloxacin (MXF) hydrochloride, featuring the unique aggregation-induced emission (AIE) characteristics. By taking advantage of their AIE feature, antibiotic metabolism in cells could be in situ visualized, which clearly shows that the luminescent aggregates accumulate in the lysosomes. Moreover, after a structure-activity relationship study, we found an ideal site of MXF to be modified with a triphenylphosphonium and an antibiotic derivative MXF-P was prepared, which is able to specifically differentiate bacterial species after only 10 min of treatment. Moreover, MXF-P shows highly effective broad-spectrum antibacterial activity, excellent therapeutic effects and biosafety for S. aureus-infected wound recovery. Thus, this work not only discovers the multifunctionalities of the antibiotics but also provides a feasible strategy to make the commercialized drugs more powerful.
A biomimetic gradient porous cage with a micro-structure for enhancing mechanical properties and accelerating osseointegration in spinal fusion
Authors: Cheng-Qi Jia, Zhen Zhang, Shi-Qi Cao, Tian-Jiao Wang, Hai-Chao Yu, Wen-Xiang Wang, Bo-Min Guo, Xiong-Ying Qiu, Yong-Gang You, Fan-Qi Hu, Jun Zhao, Xue-Song Zhang
Journal: Bioactive Materials (2022)

Spinal fusion is a widely employed treatment of patients with degenerative disc disease, in which a cage is used to replace the disc for spinal fusion. But it often fails for insufficient mechanical strength and poor osseointegration. Here, we designed a polyether-ether-ketone (PEEK)/tantalum (Ta) composite cage with a biomimetic gradient porous micro-structure, simultaneously enhancing mechanical properties and accelerating osseointegration in spinal fusion.In the study, based on the mechanical performances of PEEK and osteogenic potential of Ta, and the three-dimensional (3D) structures of cuttlebone and vertebra, the cages were respectively 3D printed by pure PEEK, PEEK with 5 wt% Ta (PEEK/Ta-5), PEEK with 10 wt% Ta (PEEK/Ta-10) and PEEK with 15 wt% Ta (PEEK/Ta-15), then verified in vitro and in sheep cervical fusion model systematically.Vertebral Gyroid structure PEEK/Ta-15 cage exhibited superior mechanical properties than Cuttlebone-like structure PEEK/Ta-15 cage, closer to the cervical vertebra. Furthermore, PEEK/Ta-15 cage with higher Ta microparticles in PEEK provided a biomimetic gradient porous micro-structure with higher surface energy, guiding cell biological behavior, promoting new bone penetration, and accelerating osseointegration in vivo.In conclusion, the study designed a biomimetic gradient porous cage with a micro-structure for enhancing mechanical properties, accelerating osseointegration and forming an anatomical lock in the fusion segment through composites, mechanical efficiency, surface extension, and pores.
Zanubrutinib in patients with previously treated B-cell malignancies intolerant of previous Bruton tyrosine kinase inhibitors in the USA: a phase 2, open-label, single-arm study
Authors: Mazyar Shadman, Ian W Flinn, Moshe Y Levy, Ryan F Porter, John M Burke, Syed F Zafar, Jamal Misleh, Edwin C Kingsley, Habte A Yimer, Benjamin Freeman, Subramanya S Rao, Arvind Chaudhry, Praveen K Tumula, Mitul D Gandhi, Sudhir Manda, Dih-Yih Chen, Kunthel By, Linlin Xu, Ye Liu, Rocco Crescenzo, Adam Idoine, Xiaoping Zhang, Aileen Cohen, Jane Huang, Jeff P Sharman
Journal: The Lancet Haematology (2022)
Prevalence of gender dysphoria and suicidality and self-harm in a national database of paediatric inpatients in the USA: a population-based, serial cross-sectional study
Authors: Hannah K Mitchell, Garrett Keim, Danielle E Apple, Elle Lett, Annie Zisk, Nadia L Dowshen, Nadir Yehya
Journal: The Lancet Child & Adolescent Health (2022)
Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis
Authors: Jingxuan Quek, Kai En Chan, Zhen Yu Wong, Caitlyn Tan, Bryan Tan, Wen Hui Lim, Darren Jun Hao Tan, Ansel Shao Pin Tang, Phoebe Tay, Jieling Xiao, Jie Ning Yong, Rebecca Wenling Zeng, Nicholas W S Chew, Benjamin Nah, Anand Kulkarni, Mohammad Shadab Siddiqui, Yock Young Dan, Vincent Wai-Sun Wong, Arun J Sanyal, Mazen Noureddin, Mark Muthiah, Cheng Han Ng
Journal: The Lancet. Gastroenterology & hepatology (2022)